tbuckley/cabot-search huggingface dataset:
Abstract 12017: The Prognostic Role of Genotypic Variants of ACE2 and TMPRSS2 Polymorphisms in SARS-CoV2 / COVID-19 Infection
Authors: Francesco Fioretti, Antonio Maria Sammartino, Francesco Ravasio, Angelica Praderio, Lorenza Inama, Matteo Pagnesi, Francesco Pallotti, Savina Nodari
Journal: Circulation (2022)

BACKGROUND: the entry of the SARS-CoV-2 into cells is mediated by the binding between the virus Spike-glycoprotein and the membrane ACE2-receptor (ACE2-R). When SARS-CoV-2 binds to ACE2-R, a down-regulation of these receptors occurs, playing a crucial role in the inflammatory response. A dysregulation of the RAAS linked to a different expression of ACE2-R and TMPRSS2 gene polymorphisms and different levels of serum ACE2 (sACE2), could be associated with abnormal inflammatory and immune response to SARS-CoV-2 infection. AIM OF THE STUDY: we aimed to verify whether there is an association between the clinical course of COVID-19 pts and the presence of more frequent ACE2 and TMPRSS2 single-nucleotide polymorphisms (SNPs) and if sACE2 levels are related to specific ACE2 and TMPRSS2 polymorphic variants. Methods: we consecutively enrolled subjects with previous documented SARS-CoV-2 infection and divided our sample into three groups: pts with asymptomatic course; pts with symptomatic course without an hospitalization for COVID-19; pts with severe symptomatic course requiring hospitalization in ICU. Data about age, clinical course, comorbidities, and therapies were collected. Blood samples were taken for the genetic analysis of the most frequent SNPs of the ACE2-R and TMPRSS2 detected in Italian population, in particular genotypic variants TT and CC of ACE2 SNPs 1 and 5 (5% and 14% respectively) and genotypic variants TT and CC of TMPRSS2 SNPs 2 and 3 (rate of 50% and 30% respective). Results: among 178 pts enrolled up to March 2022, we have so far analyzed the genetic polymorphisms of 74 pts; 21 (28%) were hospitalized for COVID-19, 38 (51%) had symptomatic course without hospitalization and 15 (21%) were completely asymptomatics. We found that sACE2 levels were higher in genotypic variant CC of SNP 1 of TMPRSS2 gene. Considering that a high concentration of sACE2 outlines a proinflammatory condition, it could be hypothesized that the CC genotype may be a predisposing condition to the cytokine storm of COVID-19. PERSPECTIVES: Genetic analysis of ACE2 and TMPRSS2 SNPs will help to clarify the relationship between these polymorphic variant, sACE2 levels, risk of SARS-CoV2 infection and severity of clinical presentation of COVID-19 in pts with or without CV diseases.
Abstract 11978: Composite Deep Learning ECG Algorithm Trained to Identify Structural Heart Diseases Can Identify Clinically Ascertained Hypertrophic Cardiomyopathy
Authors: Greg Lee, Martin Kang, Alvaro Ulloa Cerna, Dustin Hartzel, Daniel Rocha, Arun Nemani, Brandon Fornwalt, Ruijun Chen, John Pfeifer, Christopher M Haggerty
Journal: Circulation (2022)

Introduction: A deep learning ECG algorithm, rECHOmmend, can accurately identify patients with any of seven structural heart diseases: five valvular diseases, low ejection fraction and interventricular septal (IVS) thickening. Components of the rECHOmmend composite label (IVS&gt;15mm, mitral regurgitation) are also associated with hypertrophic cardiomyopathy (HCM). We hypothesized that despite being trained without HCM-specific labels, rECHOmmend can reliably identify HCM patients and achieve comparable performance to an HCM-specific classifier. Methods: Algorithms were developed from 2,898,979 ECGs acquired from 661,366 patients between 1984-2021. rECHOmmend was trained on a composite label derived from echocardiography and electronic health record (EHR) data. This ensemble model consists of 7 disease specific models with an aggregate model to predict a composite structural heart disease endpoint with shared clinical actionability. Separately, an HCM-specific model was trained on a binary label derived from EHR. To enable comparison, both classifiers were tested on a shared ECG holdout set (ECG prevalence 1.24%, patient prevalence 0.52%). Results: Despite being trained without HCM specific labels, the rECHOmmend ensemble showed comparable performance to a HCM-specific classifier (C-statistic: 0.92 [0.90-0.93] vs 0.90 [0.89-0.91]). At an operating point optimized for the F1-score, the sensitivity to HCM was higher for rECHOmmend at 0.42 [0.33-0.50] compared to 0.18 [0.15-0.21] for the HCM-specific classifier. rECHOmmend sustained performance across a range of IVS thicknesses, suggesting it was not solely reliant on IVS thickening for HCM identification and other ensemble components contributed to performance. Conclusions: A composite deep learning algorithm trained to identify structural heart diseases can identify clinically ascertained HCM with good performance, despite being trained without HCM-specific labels.
Abstract 12239: Objectively Measured Physical Activity Decreases the Risk of Subclinical Cardiovascular Disease: A Systematic Review
Authors: Aparna Narendrula, Ellen Brinza, Christine Horvat Davey, Allison R Webel, Chris T Longenecker
Journal: Circulation (2022)

Introduction: Physical activity (PA) decreases the risk of cardiovascular events, but to what degree this is related to effects on surrogate markers of subclinical cardiovascular disease (CVD) is unclear. Clarifying the relationship between objectively measured PA and subclinical CVD would provide justification for using measures of subclinical CVD in clinical trials of PA interventions. Hypothesis: We hypothesized that higher levels of objectively measured PA are associated with less subclinical CVD. Methods: We performed a systematic review using Medline, Embase, CINAHL and Cochrane (January 1, 2000 - January 12, 2022). Studies of adult populations that examined the relationship between objectively measured PA (accelerometry) and subclinical CVD were included. Markers for subclinical CVD included: ankle brachial index ( n =4 studies); arterial stiffness ( n =31); carotid artery plaque/stenosis and intima media thickness ( n =9); coronary artery atherosclerosis ( n =4); endothelial function ( n =8); measures of cardiac structure and function ( n =4); and eight studies included multiple of the aforementioned outcomes. For those studies, we considered results on each outcome separately. Risk of bias was also assessed. Results: PA was inversely associated with subclinical CVD in 60 of 78 included analyses (76.9%). Of these, five studies (6.4%) found only an association with higher levels of PA. In six studies (7.7%), PA was no longer associated with subclinical CVD after adjustment for confounders. Seven analyses (9.0%) demonstrated mixed results but demonstrated an inverse relationship between PA and subclinical CVD in specific circumstances. Only 18 studies (23.1%) suggested that PA was not associated with decreased subclinical CVD. Conclusions: Increased PA is associated with less subclinical CVD across diverse populations. Interventions to increase PA have the potential to reduce the burden of subclinical CVD and, therefore, clinical CVD events.
Abstract 12106: Electrocardiographic Imaging Accuracy and Coherence Between Two Different Systems
Authors: Leonor Parreira, Pedro Carmo, Dinis Mesquita, Rita Marinheiro, Lia Marques, Sofia Mancelos, Rebecca Hitchen, Antonio Ferreira, Mikhail Chmelevsky, Stepan Zubarev, Pedro Araujo Goncalves, Hugo Marques, Pedro Adragao
Journal: Circulation (2022)

Introduction: Previous studies reporting on electrocardiographic imaging (ECGI), using an epicardial-only system, have suggested a bad accuracy Hypothesis: Assess the accuracy and coherence of two endo-epicardial ECGI systems using different cardiac sources. Methods: We performed 61 ECGI procedures in 48 patients referred for ablation of frequent idiopathic premature ventricular contractions (PVCs) at our center. The Amycard (EP Solutions SA, Switzerland) system based on the extracellular potential, was used in 26 patients, the VIVO (Catheter Precision, NJ USA) systems based on the equivalent double layer model in 9, and both in 13 patients. The localisation of the PVCs based on ECGI was done using a segmental model with 22 segments on the left ventricle, to include the classical 17 segment model plus the aortic cusps and the papillary muscles, and 12 segments on the right ventricle including 4 on the right ventricular outflow tract (RVOT). A perfect match (PM) was defined as a predicted location within the same anatomic segment, whereas a near match (NM) as a predicted location within the same segment or a contiguous one. Results: Ablation was performed in 42 patients, successful in 76%. The origin of the PVCs was the RVOT in 22 patients, right ventricle in 5, coronary cusps in 3, left ventricle in 3, LV summit in 3, LVOT in 2, papillary muscles in 2, moderator band in 1 and aortomitral continuity in 1. The agreement between the predicted site and the invasive mapping with both systems is depicted in the table. The percentage of PM and NM was not significantly different. In the 13 patients that had the ECGI performed with both systems, we found a NM in 100% and a PM in 70%. (Figure). Conclusions: ECGI is an accurate diagnostic tool with reproducible results regardless the cardiac source used for analysis.
Abstract 11750: Disparities Among Covid-19 Mortality in Patients With Concurrent Cancer and Cardiovascular Disease in 2020: A Nationwide Analysis
Authors: Jacqueline T Vuong, Daniel Addison, Mary Branch, Sherry-Ann A Brown, Nausheen Akhter, Sarju Ganatra, Tochi Okwuosa, Mamas Mamas, Harriette G Van Spall, Eric H Yang
Journal: Circulation (2022)

Introduction: The COVID-19 pandemic has highlighted important socioeconomic health disparities in the United States. Both cardiovascular disease (CVD) and cancer are associated with worse COVID-19 outcomes. We describe racial or ethnic, sex, and rural disparities in mortality rates from COVID-19 in the US cardio-oncology (C-O) population with concurrent cancer and CVD. Methods: Using the multiple causes of death data files within CDC WONDER, we assessed survival outcomes from March to December 2020 (most intense for COVID-19 deaths) by race or ethnicity, sex, and rural status. C-O populations were defined as having ICD 10 codes C00-C97 for “malignant neoplasms” and ICD 10 codes I10-I15 for “hypertensive heart disease”, I20-I25 for “ischemic heart disease” I30-I51 for “other forms of heart disease” encompassing valvular disorders, cardiac arrythmias, myocarditis, and heart failure &amp; cardiomyopathies, or I70 for peripheral atherosclerosis listed as contributing causes of death. In this population, those with ICD 10 code U07.1 for “COVID-19” listed as an underlying cause of death were included. Age-adjusted mortality rates (AAMR) were calculated based on contemporary US population standards. Results: Overall, there were 6,311 deaths from COVID-19 among 16,282 all-cause deaths in the C-O population (AAMR 5.17 deaths/1,000,000 person-years; 95% CI 5.04-5.29). These deaths comprised 1.80% of all COVID-19 deaths (total 350,831) in the study period. Mortality rates were higher in men than women (AAMR 7.35 vs 3.44 deaths/1,000,000; HR 2.13, p&lt;0.0001). Among racial or ethnic groups, mortality rates were highest among African Americans (AAMR 9.31 deaths/1,000,000; 95% CI 8.75-9.88), and higher among Hispanic than non-Hispanic Americans (AAMR 7.10 vs 4.86 deaths/1,000,000; HR 1.46, p&lt;0.0001). Mortality rates were higher in rural areas than metropolitan areas (crude mortality rate 9.15 vs 6.20 deaths/1,000,000; HR 1.48, p &lt;0.001). Conclusion: Among cancer patients with concurrent CVD, COVID-19 deaths were disproportionately higher in male, African American, Hispanic, and rural patients. Further research is needed to understand socioeconomic factors underpinning these disparities and design interventions to improve patient outcomes.
Abstract 12318: Echocardiographic or Blood Pressure Screening of Women With Past Pre-Eclampsia and Gestational Hypertension: The Western Health Survey of Heart Failure Risk After Pregnancy Hypertension Pilot Survey
Authors: Jonathan Sen, Jordan Dixon, Emma Smith, Sam Banks, Ashleigh-Georgia Sherriff, Lee-Anne Lynch, Leah Wright, Marc Oreto, Joanne Said, Thomas Marwick
Journal: Circulation (2022)

Introduction: Pre-eclampsia (Pec) and gestational hypertension (GHT) are potential explanations for the female preponderance of heart failure with preserved ejection fraction. How and when to use this information clinically is unclear. Hypothesis: We hypothesized that subclinical disturbances of left ventricular (LV) structure and function (stage B heart failure, SBHF) are more common at 5-10 years post-partum in women with a history of Pec compared with women with GHT or uneventful pregnancies. Methods: The proportion of SBHF were compared between 25 women with Pec, 16 with GHT or normal pregnancy. Sub-group analysis comparing patients with and without hypertension at follow-up were also conducted. Results: Among 41 participants (age 40±6 years), followed at 9 years, SBHF was reported in 35% participants with Pec and 53% with GHT ( p =0.32). Diastolic blood pressure was significantly higher in patients with SBHF than without (94±21 vs. 81±13 mmHg, p=0.035), and a similar trend was observed with systolic blood pressure (147±42 vs. 128±22mmHg, p=0.099). SBHF was observed in 6 (55%) of 11 pts with hypertension at follow-up, but only in 7 (32%) of 22 without ( p =0.27). Mean LV end-diastolic volume (117.2±19.1 vs. 93.3±13.1mL, p =0.03), LV end-systolic volume (51.9±7.5 vs. 42±7 mL, p= 0.04), LV mass index (73±8.6 vs. 67.3±14.6mmHg, p=0.41), E/e’ (Sept: 9.7±2.7 vs. 7.5±1.7, p =0.009; Lat: 7.4±2.6 vs. 5.5±1.7, p =0.02) were higher in participants with hypertension than without. Conclusions: 9 years after pregnancy, SBHF was prevalent in pts with both previous Pec and GHT, but was not significantly different between the entities. Echocardiographic screening may add little to blood pressure follow-up in the identification of HF risk.
Abstract 11199: Disparities in Screening for Postpartum Depression - Insights From American Heart Association Research Goes Red Registry
Authors: Yaa A Kwapong, Ellen Boakye, Pratheek Mallya, Juan Zhao, William Akel, Pamela Ouyang, Roger S Blumenthal, Abha Khandelwal, Claire Kinzy, Laxmi S Mehta, Veronique L Roger, Jennifer L Hall, Garima Sharma
Journal: Circulation (2022)

Introduction: Postpartum depression (PPD) affects 1 in 5 women in the United States and is associated with cardiovascular disease. Disparities in PPD screening have not been well studied. We investigated the level of self-reported screening, diagnosis of PPD, and disparities in screening. Methods: We utilized data from participants enrolled in the AHA Research Goes Red Registry, an online research platform powered by Verily, who responded to the Fertility and Pregnancy survey. Of the 3128 women who had responded as of May 2022, 311 participants were self-identified as postpartum women and were included in this analysis. The definition of postpartum in the survey was “I have been pregnant within the last 12 months ”. The survey included questions on PPD screening and diagnosis. We used chi-squared testing to examine differences by race-ethnicity, education, income, and proximity to healthcare in PPD screening. Results: Among the 311 postpartum women (mean age: 33.3 ± 4.8 years), 83% recalled being screened for PPD. Of the 311 women, 15% reported a diagnosis of PPD, of which 92% received treatment. There were no significant differences in PPD screening by race-ethnicity: non-Hispanic White (82%), non-Hispanic Black (83%), Asian (88%), Hispanic (80%) (p=0.91), possibly limited by sample size (Fig 1a). Similarly, there were no significant differences by educational status (p=0.22) (Fig 1b) or income (p=0.53) (Fig 1c). Women who lived in a big city with access to many hospitals had higher proportion of screening (88%), while rural area dwellers had the least (74%, p=0.54) (Fig 1d). Conclusion: Among this multiracial cohort of postpartum women, the prevalence of self-reported screening and diagnosis of PPD was 83% and 15%, respectively. The prevalence of screening did not significantly differ by race-ethnicity, education, income, and proximity to healthcare. Future larger studies were suggested to explore screening of PPD by race and other social determinants of health.
Abstract 11530: Edoxaban For Pediatric Patients With Cardiac Diseases: A Randomized, Open Label, Multicenter Study
Authors: Michael A Portman, Jeffrey P Jacobs, Jane W Newburger, Felix Berger, Michael A Grosso, Anil C Duggal, Neil A Goldenberg
Journal: Circulation (2022)

Introduction: Standard of care (SOC) anticoagulation for thromboembolism (TE) prevention in patients &lt;18 years old with cardiac disease includes low molecular weight heparins or vitamin K antagonists. Limited data exist comparing direct oral anticoagulants as edoxaban with conventional anticoagulants in this population. Hypothesis: Edoxaban is at least as safe as the current standard-of-care (low molecular weight heparins and/or vitamin K antagonists) with regard to the incidence of major and clinically relevant nonmajor bleeding in pediatric patients with cardiac diseases at risk of thromboembolism. Methods: We performed a phase 3, multinational, prospective, randomized, open-label, blinded-endpoint trial in patients &lt;18 years old with cardiac disease (ENNOBLE-ATE, NCT00687882). Children were randomized 2:1 to age- and weight-based oral edoxaban once-daily versus SOC for 3 months (main study). Randomization was stratified by concomitant use of aspirin and by underlying disease groups, as follow: history of Fontan procedure; Kawasaki disease; heart failure; other. Both groups continued in an extension with edoxaban through 1 year. The primary endpoint was adjudicated International Society on Thrombosis and Haemostasis defined clinically-relevant bleeding (CRB). The main secondary endpoint was a composite of symptomatic TE and asymptomatic intracardiac thrombosis. Results: We randomized 168 children from May 2018 to September 2021. The CRB event rates were similar between groups during the main period. One subject per group experienced a nonmajor CRB. Treatment-emergent adverse events occurred in 46.8% (51/109) with edoxaban and 41.4% (24/58) with SOC. One SOC subject experienced 2 TE events (DVT with PE). In 152 subjects continuing in the extension, one CRB event (0.7%; trauma related) and 4 TEs occurred (2.8%; 2 strokes and 2 coronary artery thromboses and/or myocardial infarctions). Conclusion: Bleeding and TE occurred rarely for both groups and during the extension,suggesting that edoxaban is safe and effective for TE prevention in this population. Once daily edoxaban may provide advantage for children considering difficulties with enoxaparin injections and food and drug interactions with warfarin.
Abstract 12145: Cell Surface Trafficking and Functional Deep Mutational Scans of the Potassium Channel Gene KCNE1
Authors: Ayesha Muhammad, Tao Yang, Maria Calandranis, Lynn Hall, Kenneth A Matreyek, Douglas M Fowler, Dan M Roden, Andrew M Glazer
Journal: Circulation (2022)

Introduction: Loss of function variants in KCNE1 cause type 5 Long QT Syndrome. Deep mutational scanning is a highly multiplexed method to assay the function of thousands of genetic variants. Hypothesis: A deep mutational scan of KCNE1 will identify variants that disrupt KCNE1 function and may lead to Long QT Syndrome. Methods: A comprehensive library of nearly all possible KCNE1 variants was generated by inverse PCR. The library was integrated in a one-variant-per-cell format into HEK293 landing pad cells expressing the KCNE1 partner KCNQ1 . To assess surface trafficking, cells expressing an HA-tagged KCNE1 variant library were stained with an anti-HA antibody, FACS sorted into 4 equal bins, and deep sequenced. For each variant, a weighted average of variant counts across the 4 bins was calculated. To assess channel function, the KCNE1 library was introduced into landing pad cells expressing a gain of function S140G KCNQ1 variant, which causes KCNE1-dependent K+ efflux and cell death, for 12 days. Functional scores for each variant were calculated as a normalized ratio of initial and day 12 counts. Results: The KCNE1 library had 88% of 2,451 possible missense variants. The results of the 2 assays indicate that the KCNE1 C-terminus is dispensable for trafficking but not function. Missense variant trafficking scores (n=1,886) were normally distributed (0.93+/-0.37, mean+/-SD); 277 loss- and 183 gain-of-trafficking variants were identified. Missense variant functional scores were bimodally distributed. The functional assay identified loss of function variants with trafficking-deficient or trafficking-normal scores (likely gating variants). The assays identified structurally important regions, such as an N-terminal salt bridge, a transmembrane helix at residues 47-59 resistant to hydrophilic variants, and a cytoplasmic amphipathic helix at residues 90-114 resistant to hydrophobic variants. Manual patch clamp results for 4 previously studied and 4 novel variants correlated with deep mutational scanning scores. Conclusions: Two deep mutational scans of KCNE1 identified variants that disrupt channel or function. This dataset elucidates structure-function relationships and may help predict LQT5 variant pathogenicity.
Abstract 11527: Regional Variation in Cardiovascular Genes Enables a Tractable Genome Editing Strategy
Authors: Vikki A Krysov, Rachel H Wilson, Nicholas S Ten, Nathan Youlton, Hannah N De Jong, Shirley Sutton, Yong Huang, Chloe Reuter, Megan E Grove, Matthew T Wheeler, Euan A Ashley, Victoria N Parikh
Journal: Circulation (2022)

Recent rise in the number and therapeutic potential of genome engineering technologies has generated excitement in cardiovascular genetics. One significant barrier to their implementation is costly and time consuming reagent development for novel unique variants. Prior data have illuminated the potential for regional clustering of disease-causing genetic variants in known and potential novel functional protein domains. We hypothesized that most cardiovascular disease-relevant genes in ClinVar would display regional variant clustering, and that multiple variants within a regional hotspot could be targeted with limited prime editing reagents. We collated 2,471 high confidence pathogenic or likely pathogenic (P/LP) missense and truncating variants from 111 cardiovascular disease genes. We then defined a regional clustering index (RCI), the percent of P/LP variants in a given gene located within a pre-specified window around each variant. At a window size commensurate with maximally reported prime editing extension length, 78bp, we found that missense variants displayed a higher mean RCI than truncating variants. We next identified genes particularly attractive for pathogenic hotspot-targeted prime editing with at least 20 P/LP variants and observed that the mean RCI in missense variants remained higher than for truncating variants and for rare variants observed in the same genes in gnomAD (Mean±SD RCI 78bp : P/LP ClinVar Missense=5.2±5.9%; P/LP ClinVar Truncating=2.1±3.2%, gnomAD Missense=2±3.2%, gnomAD Truncating=1.1±2.4%. p&lt;2.2e-16; ANOVA with post hoc Bonferroni correction). Further, we tested the feasibility of prime editing for multiple variants in a single hotspot in KCNH2, a gene with a high mean missense variant RCI. Sixty variants were induced in this hotspot in HEK293 cells with CRISPR-X. Correction of these variants was attempted with prime editing using two overlapping prime editing guide RNA extensions. The mean prime editing efficiency across CRISPR-X-enriched variants within this hotspot was 57±27%, including 3 P/LP variants. These data underscore the utility of pathogenic variant hotspots in the diagnosis and treatment of inherited cardiovascular disease.